본문 바로가기
HOME> 논문 > 논문 검색상세

논문 상세정보

Journal of molecular biology v.429 no.22, 2017년, pp.3546 - 3560   SCI SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

Generation and Validation of Intracellular Ubiquitin Variant Inhibitors for USP7 and USP10

Zhang, Wei (Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada ) ; Sartori, Maria A. (Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada ) ; Makhnevych, Taras (Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada ) ; Federowicz, Kelly E. (<ce:sans-serif>Cancer Epigenetics DPU, Oncology</ce:sans-serif>Research & Development<ce:sans-serif>, GlaxoSmithKline Inc, 1250 S. Collegeville Road, Collegeville, PA 19426, USA</ce:sans-serif> ) ; Dong, Xiaohui (<ce:sans-serif>Department of Aquaculture, Fisheries College, Guangdong Ocean University, Guangdong, 524088, China</ce:sans-serif> ) ; Liu, Li (<ce:sans-serif>Department of Marine Biology, Fisheries College, Guangdong Ocean University, Guangdong, 524025, China</ce: ) ; Nim, Satra ; Dong, Aiping ; Yang, Jingsong ; Li, Yanjun ; Haddad, Dania ; Ernst, Andreas ; Heerding, Dirk ; Tong, Yufeng ; Moffat, Jason ; Sidhu, Sachdev S. ;
  • 초록  

    Abstract Post-translational modification of the p53 signaling pathway plays an important role in cell cycle progression and stress-induced apoptosis. Indeed, a large body of work has shown that dysregulation of p53 and its E3 ligase MDM2 by the ubiquitin-proteasome system (UPS) promotes carcinogenesis and malignant transformation. Thus, drug discovery efforts have focused on the restoration of wild-type p53 activity or inactivation of oncogenic mutant p53 by targeted inhibition of UPS components, particularly key deubiquitinases (DUBs) of the ubiquitin-specific protease (USP) class. However, development of selective small-molecule USP inhibitors has been challenging, partly due to the highly conserved structural features of the catalytic sites across the class. To tackle this problem, we devised a protein engineering strategy for rational design of inhibitors for DUBs and other UPS proteins. We employed a phage-displayed ubiquitin variant (UbV) library to develop inhibitors targeting the DUBs USP7 and USP10, which are involved in regulating levels of p53 and MDM2. We were able to identify UbVs that bound USP7 or USP10 with high affinity and inhibited deubiquitination activity. We solved the crystal structure of UbV.7.2 and rationalized the molecular basis for enhanced affinity and specificity for USP7. Finally, cell death was increased significantly by UbV.7.2 expression in a colon cancer cell line that was treated with the chemotherapy drug cisplatin, demonstrating the therapeutic potential of inhibiting USP7 by this approach. Highlights Potent and selective inhibitors were developed for USP7 and USP10. Crystal structure of UbV.7.2 sheds light on binding and inhibition mechanism. UbV.7.2 destabilizes MDM2 and stabilizes p53. UbV.10.1 affects p53 localization and induces p53 degradation. UbV.7.2 enhances DNA-damage-induced cancer cell death. Graphical Abstract [DISPLAY OMISSION]


  • 주제어

    USP7 .   USP10 .   p53 .   inhibitor design.  

 활용도 분석

  • 상세보기

    amChart 영역
  • 원문보기

    amChart 영역

원문보기

무료다운로드
  • 원문이 없습니다.
유료다운로드

유료 다운로드의 경우 해당 사이트의 정책에 따라 신규 회원가입, 로그인, 유료 구매 등이 필요할 수 있습니다. 해당 사이트에서 발생하는 귀하의 모든 정보활동은 NDSL의 서비스 정책과 무관합니다.

원문복사신청을 하시면, 일부 해외 인쇄학술지의 경우 외국학술지지원센터(FRIC)에서
무료 원문복사 서비스를 제공합니다.

NDSL에서는 해당 원문을 복사서비스하고 있습니다. 위의 원문복사신청 또는 장바구니 담기를 통하여 원문복사서비스 이용이 가능합니다.

이 논문과 함께 출판된 논문 + 더보기